A first-in-class HER2-targeted radiopharmaceutical therapy: Initial findings from the Phase 0/1 HEAT trial of 177Lu-RAD202 in HER2+ advanced solid tumors

Background: HER2-targeted therapies have transformed outcomes for HER2-expressing solid tumors, improving survival in breast, lung, and gastric cancers and gaining accelerated approval in biliary tract, bladder, and colon cancers. Nonetheless, primary and acquired resistance remain major challenges. 177Lu-RAD202 is a Lutetium-177-labeled camelid single-domain antibody (sdAb) targeting HER2, developed for treating HER2-positive (HER2+) solid tumors. The small sdAb enables deep tumor penetration and rapid clearance, while 177Lu emits cytotoxic beta-radiation producing a bystander effect independent of receptor density. A Phase I diagnostic study with 99mTc-RAD202 demonstrated safety, as well as favorable biodistribution and imaging characteristics (tumor targeting) in 10 patients with HER2+ breast cancer. 177Lu-RAD202 may overcome resistance to monoclonal antibody, tyrosine kinase inhibitor, and antibody-drug conjugate (ADC) therapies, supporting further clinical evaluation. Methods: The HEAT Trial (NCT06824155) is a first-in-human, open-label, multicenter Phase 0/1 multiple dosing study of 177Lu-RAD202 in HER2+ advanced solid tumors. Phase 0 involves a single 10 mCi (0.37 GBq) intravenous dose with serial SPECT/CT imaging for biodistribution, dosimetry, and tumor uptake. Phase 1 includes escalating therapeutic doses, commencing at 30 mCi (~1.1 GBq; Dose Level [DL] 1) with planned increases as per Bayesian Optimal Design. The trial is currently enrolling patients at a therapeutic dose of 75 mCi. Additional dose levels will be explored. Primary objectives are to evaluate safety, clinical activity, tumor targeting and determine the recommended therapeutic dose(s). Results: As of November 2025, three participants with HER2+ solid tumors have been treated at 30 mCi. Lesion dosimetry demonstrated targeted 177Lu-RAD202 uptake across multiple metastatic sites, including visceral, subcutaneous, breast, lymph node, and skin lesions. Absorbed doses reached up to 3.6 Gy per lesion at 30mCi. No serious treatment-related adverse events (AEs) occurred. Two treatment-related Grade 1 AEs (dysgeusia, pleural effusion) were reported in one participant. Overall safety has been favorable, with few low-grade (Grade 1-2) treatment-emergent AEs. Conclusion: These early first-in-human data demonstrate high tumor uptake and favorable safety of 177Lu-RAD202, supporting continued dose escalation. This HER2-targeted radiotherapeutic potentially offers a novel treatment approach for HER2+ solid tumors, including breast, non-small cell lung and gastric cancer. Updated results from DL2 (75 mCi) and higher will be presented at the congress.